Arousal is a vital protective mechanism in infants when confronted with potentially life-threatening hypoxia during sleepwhether from airway obstruction, rebreathing, apnea, or circulatory failure. Our focus is on the descending, or subcortical, arousal pathways that modulate breathing, spinal motor activity, and sympathetic activity that controls body temperature, heart rate, and blood pressure. We now know that 70% of SIDS infants have decreased 5-HT1A receptor and serotonin transporter (5-HTT) binding, expressed per 5-HT neuron, and increased numbers of 5-HT neurons, in medullary regions important for modulating arousal, motor activity, body temperature, heart rate, and breathing. Medullary 5-HT neurons also receive excitatory orexinergic and inhibitory GABAergic inputs that by themselves have important roles in arousal. We propose that SIDS infants are at risk because of abnormalities in medullary serotonergic (5-HT) function that lead to altered modulation of descending pathways essential for coordinated and effective arousal, and that death results from a combination of impaired arousal mechanisms and extrinsic stressors that occurs during a critical stage of development and typically during sleep. In the analysis of defective arousal mechanisms in SIDS, it is important to consider that many SIDS infants have repeated episodes of apnea and hypoxia in the days or weeks prior to death. We propose that repeated exposure to subclinicai hypoxia leads to arousal habituation. Habituation refers to the waning over time of a physiological response to repetitive stimuli in order to prevent inappropriate responses to non-dangerous or non-important stimuliyet habituation of arousal from sleep to a dangerous stimulus such as severe intermittent hypoxia could lead to disastrous consequences. In this project, we will define the characteristics of subcortical arousals during development in the rat and test the novel hypothesis that excessive habituation is a major contributor to dysfunctional arousals. We will further determine whether effective arousal from sleep in response to hypoxia is affected by the manipulation of the 5-HT1A and GABAA receptor and the 5-HTT, chronic exposure to intermittent hypoxia, overheating and fever, and prenatal exposure to tobacco smoke. Our focus upon the poorly understood function, pathophysiology, and neuroanatomy of subcortical arousal, including its interaction with thermoregulation, is a major strength of this project. The results of these studies will provide key information about the role of serotonin in arousal mechanisms and identify important links between intermittent exposure to hypoxia, serotonin, arousal, and SIDS. This information will be critical and lead toward ultimately understanding the pathophysiological mechanisms of SIDS and developing therapeutic interventions to eradicate all SIDS deaths.